beta-alkyl choline salts and intermediates and processes for their production



Patented Feb. 13, 1940 UNITED" s A Es p-ALKYL CHOLlNE'SALTS'iAND-INTERMEDI- r ATES AND PROCESSES FOR THEIR PRO- DUCTIONRandolph 'T. Major, Bonnett, Rahway,

Plainfield, and Howard T. N. 3., assignors=tozMerck &

00., Inc.', Rahway N. J., a corporation of New I Jersey 1 No Drawing.Original application, July is, 1935,

Serial No. 30,150. Dividedcand thisapplication January 23, 1937, SerialNo. 121,980

rename.- ..(01. 260-584) This is a division of application Serial No.30,150, filed July 6, 1935. I

This invention relates broadly to processes for preparingfi-alkyl-choline iodides and salts of acids whose silver saltsare moresoluble than silver iodide (specificaly exemplified 'byprocesse's forthe production of fi-methyl-choline chloride), and relating moreparticularly to: optical isomers thereof and methods fortheirpreparationl Patent No. 2,040,145, issued May 12, 1936, to (meetus, Randolph T. Major, in associationwith Joseph K. Cline, relates tothe preparation of the racemic formof e-rnethyl choline chloride.

Theoreticallmit should be possible, toprepare two optically active formsof this and related choline compoundswhen they contain an asymmetriccarbon atom.' Sinceit is generally recognized that one of the opticalisomers of a medicinal chemical is usually much more active physi- 0.ologically than the other, it was considereddesirable to attempt theproduction of the theoretically possible optical isomers. 1

Pharmacological tests with the optical isomers of pmethyl cholinechloride show that the physi-- ological action of the d-form is strongerthaneven the racemic form; whereas the laevo form is considerablymilder. Thus the production and isolation of ,bothforms, together withthe known racemic form, afford to the medical profession a much widerrange for accurate dosage and control with these highly potent drugs.The results of our experiments indicate that the most satisfactorymethod of producing these isomers, is to prepare them from thecorresponding optical. isomers obtained by resolving the racemicdimethylaminoisopropanol by appropriate means, as will further appear,into its dand l-forms, and to convert them, respectively, into theircorresponding methyl choline iodides. Thereafter, we may prepare thechlorides or other salts from the iodides. Proceeding in this manner,the optical isomers of (i-methyl choline chloride are obtained as whitecrystalline hygroscopic solids; the d-form having a melting point of165-16'7 C. and an optical rotation,

((1) 3: 388 and the Z-form a melting point of 165-167 C. and I arotation,

(09%: 382 The process as above described may also be applied to theproduction of other salts. Obviously, such other salts of acids may bethus prepared where the acid involved is one whose silversalts are moresoluble than silver iodide.

' solution with anhydrous The following description of the more detailedsteps of Y .the process exemplifies the general method as directed-moreparticularly to the ultimate production of both optical isomers of ,8-methyl choline chloride;

Resolution of dimethylaminoisopropanol racemic and its resolution intothe dand l-forms is accomplished by usingthe following manner:

cZ-F0rm.-Dirnethylaminoisopropanol, having a boiling, point of 124-126C., is treated with-5% excess .bromo-carnphorsulfonic acid in ethyl acetate solution. he salt is recrystallized from. a mixture of 5 cc. ethylacetate and l cc. absolute alcohol per gram of salt, its rotationbecoming. constantat+835 I h I from the salt by treating the latter withan excess of NaOI-I, extracting with ether, drying theether 4 KzCOa, anddistilling at atmospheric pressure. It has a boiling point of v12415-126 C. at 770 mm.; optical rotation I (a)i5"=+l7.1.

Z-Form.-Dimethylaminoisopropanol having a boiling point of 124-126 0.,is treated with 1.05 mols of d-tartaric acidin alcohol solution.- Theysalt is recrystallized from a mixtureof 6 cc;- 96%' alcohol p er'gram ofsalt; After repeated recrystallizations, a salt is obtained havingrotation,

a g=-10.7 The laevo-amine is obtained from the salt by treating the samewith an excess of NaOH, extracting with ether, drying the ether solutionwith anhydrous K2003, and distilling at atmospheric pressure. It has aboiling point of and optical rotation about e=-15 The racemic amine mayalso be resolved into its dand Z-forms by treating it withbromocamp-horsulfonic acid to separate out the dextroform, removing thebromo-camphorsulfonic acid irom the salt, and

Preparation of dand l-fl-methylcholine iodides The methiodides of therespective amines are The-dextro-amine is obtained' prepared by treatingthe latter with methyl iodide in ether solution at room temperatures.They are recrystallized from hot absolute alcohol to which about 20%acetone is added after solution. The d-c-methylcholine iodide has amelting point of 176-177 C., and optical rotation,

the l-p-methylcholine iodide has a melting point of 176.5-177.5 0., and,

Preparation of dand l-p-methylcholine chlorides The dandZ-p-methylcholine chlorides are prepared by reacting upon the respectiveiodides with AgCl in alcohol solution. The silver salts formed in thereaction are removed by filtration.

The last traces of silver chloride are removed by passing hydrogensulfide into the solution. Charcoal is added and the mixture filtered.The filtrate is concentrated to a gummy consistency, and then the saltsare recrystallized from butyl alcohol. The d-e-methylcholine chloridehas a melting point of 165-167 C., and

(a if: +38.8

the laevo-form, a melting point of 165-167", and (a)=38.2

Preparation of dand l-p-methylcholz'ne salts Racemicdimethylaminoisopropanol Methyl iodide p-methyl-choline iodide Silversalt p-methylcholine salt It will be apparent that various modificationsI the steps of resolving dimethylaminoisopropanol into its dextroandlaevo-forms by treating the racemic form of the amine with an opticallyactive acid of the group consisting of bromocamphor sulfonic acid andd-tartaric acid, subsequently treating the optical isomers with methyliodide to form their methiodides, and thereafter converting themethiodides into the desired salts by reacting upon them with the silversalt of a corresponding inorganic acid Whose silver salt is more solublethan silver iodide.

2. The process of producing fi-methyl choline salts which comprises thesteps of treating dimethylaminoisopropanol with methyl iodide to formits methiodide, and thereafter converting the methiodide into thedesired salt by reacting upon it with the silver salt of a correspondinginorganic acid whose silver salt is more soluble than silver iodide.

3. Optically active ,d-methylcholine salts of inorganic acids whosesilver salts are more soluble than silver iodide.

4. d-p-methylcholine chloride being in the form of a white hygroscopiccrystalline solid having, in its pure form, a melting point of about165- 167 C., and optical rotation about 5. Z-p-methylcholine chloride,being in the form of a white hygroscopic crystalline solid having, inits pure form, a melting point of about l65-l67 C. and optical rotationabout tog -38.2

